Fibrosis is a pathobiological process common to many tissues and diseases which results in tissue remodeling and loss of function, often necessitating organ replacement or leading to end-stage disease. No therapies are currently available that successfully arrest or reverse fibrosis, and this represents a significant unmet clinical need. Fibrosis occurs predominantly in soft tissues (lung, liver, kidney, heart, skin) through excess fibroblast activation to a contractile/proliferative/apoptosis resistant state and accompanying deposition of extracellular matrix. We have discovered that fibroblasts are exquisitely sensitive to alterations in matrix stiffness; this finding is true for both normal and disease-derived fibroblasts, and spans the stiffness range found in normal and fibrotic lung tissue. In this project, we seek to dissect a novel molecular pathway linking matrix stiffness to fibroblast activation, and test whether this pathway is relevant in human fibrosis and essential in driving fibrosis in model systems. We focus on the transcriptional co-activators YAP and TAZ, evolutionarily conserved regulators of organ size, cell cycle, and stem cell function. Our preliminary data demonstrate enhanced nuclear localization of YAP/TAZ in human IPF tissue, and strongly support an essential role for YAP and TAZ in fibroblast activation downstream of both matrix stiffness and TGF-beta, two pivotal regulators of fibroblast biology. We hypothesize that YAP and TAZ are mechanically activated regulators of lung fibrosis that coordinate and integrate fibroblast matrix stiffness and biochemical responses leading to a cascade of pro-fibrotic functions that drive progressive fibrosis. We will evaluate this hypothesis in two aims using in vitro, mouse and human tissue models relevant to human disease. The proposed studies will advance the field by elucidating a novel point of convergence linking mechanical and biochemical cues to fibroblast activation and pulmonary fibrosis. If successful, the proposed studies could lead to new avenues for development of therapies targeting YAP and TAZ in fibrosis of the lung and other soft tissues.